Both drugs and counter ions have to meet certain demands in order to form ion pairs successfully. For hydrophilic ionized drugs, Neubert (1989) pointed out that the ideal counter ions needed to possess high lipophilicity, sufficient solubility in physiological compatibility, and metabolic stability, which was suitable for ion-pair formation and crossing lipid membranes in the form of ion pairs. The ion pairs formed by quaternary ammonium drugs and organic anions are typical examples of ion-pair formation (Takacs-Novak and Szasz 1999). Similarly, Miller et al. (2009) performed a study in which three lipophilic acidic counter ions were employed to give an understanding of the mechanism of ion-pair mediated membrane transport of low permeable drugs.

Besides ionized species, for stronger hydrogen bonds like OH∙∙∙N, the contribution of the proton transfer, OH · · · N ⇌ O⁻ · · · HN⁺, could lead to a hydrogen-bonded ion-pair formation. Sobczyk and Paweła (1974) have demonstrated the existence of proton-transfer equilibrium under appropriate conditions by measuring the dipole moment of carboxylic acid–pyridine base complexes. The results indicated that the dipole moments of these complexes were dependent on the pK _a difference (∆pK _a) between carboxylic acid and pyridine base, and large dipole moment was induced by strong interaction of ion pairs. This type of interaction depends on the following factors: (a) ∆pK _a of protonic acid and base, (b) specific complex solvation by solvent molecules, and (c) the influence of solvent expressed by its macroscopic dielectric permittivity. Based on the ion-pair model established by Huyskens and Zeegers-Huyskens (1964), it was predicted that a ∆pK _a of 3.6–6 between protonic acid and base could lead to an almost complete shift to the proton-transfer equilibrium. A recent study (Gilli et al. 2009) also showed that ion-pair formation could be reliably predicted from ∆pK _a between the donor and acceptor groups.

In theory, ion pairs are defined as binary species which exist in solution and in solid in the salt form. Such intermolecular interaction can be qualitatively inferred from the spectral characteristics. A variety of spectroscopic techniques including infrared spectroscopy (IR), nuclear magnetic resonance (NMR), ultraviolet–visible spectroscopy (UV-Vis), electron spin resonance spectroscopy (ESR), and X-ray crystallography could provide insights into ion-pair formation.

IR and NMR spectroscopy often offer experimental proofs to directly indicate the formation of ion pairs, and they are especially pronounced for hydrogen-bonded ion pairs (Barthel and Deser 1994; Biliškov et al. 2011; Habeeb 1997; Pregosin 2009). Recently, by using IR and chemical exchange two-dimensional infrared (2DIR) spectroscopy, Lee et al. (2011) investigated the contact ion pairs (CIP) assembled by Li⁺ and SCN⁻ions in N, N-dimethylformamide. In IR spectrum, the CIP formation led to a blue shift (~16 cm⁻¹) of the CN stretch frequency of Li–SCN CIP with respect to that of free SCN⁻ ion. Moreover, the temperature-dependent IR absorption spectra revealed that the CIP formation was an endothermic process. The CIP association and dissociation time constants (165 and 190 ps, respectively) were determined by chemical exchange 2DIR spectroscopy. The experimental results indicated that the ion-pair formation was a dynamic process in electrolyte solutions and in biological systems under physiological conditions. In the case of hydrogen-bonded ion pairs, a broad continuum, called as the Zundel continuum, is often observed in IR spectrum with extensive intermolecular hydrogen bonding, for which proton transfer is valuable. The broad band is caused by the strong hydrogen bonds in which a proton is distributed between the two hydrogen-bonded species by tunneling (Biliškov et al. 2011). According to the classical theory of hydrogen bond, a shift toward lower fields in the NMR spectrum is suggested as a criterion to confirm the formation of a hydrogen bond due to strong deshielding of the protons. Xi et al. (2012a, b) confirmed the formation of hydrogen-bonded ion pairs between weak acidic drugs and organic amines at 1:1 molar ratio by IR and ¹H-NMR. In this study, teriflunomide (TEF) and lornoxicam (LOX), two weak acidic drugs with OH groups, were used as the model drugs, and various organic amines including triethylamine (TEtA), diethylamine (DEtA), N-(2′-hydroxyethanol)-piperidine (NP), diethanolamine (DEA), and triethanolamine (TEA) were employed as the counter ions, whose structure was shown in Fig. 13.1. CHCl₃ and CDCl₃ solutions of TEF or LOX with or without the adding of equimolar organic amines were detected, respectively, by spectroscopic methods. In IR spectra (Fig. 13.2), the absorption at ~3,400 cm⁻¹ was assigned to stretching vibration of OH group of the two drugs. A continuum gave rise to a very broad absorption in the 3,300–2,000 cm⁻¹ range in the presence of most of organic amines. In ¹H-NMR study, compared to the signal of the proton from OH group of TEF or LOX itself (15.35 and 13.02 ppm, respectively), the proton magnetic resonance of OH in the complexes has moved toward higher field, as illustrated in Fig. 13.3. It seemed that the results were contradictory to the abovementioned classical theory of hydrogen bond in NMR. However, actually this phenomenon may be caused by strong shielding of the proton, which was a direct consequence of the intermolecular hydrogen bond interaction between drugs and organic amines instead of intramolecular hydrogen bonds in drugs. Notably, the chemical shift of OH group kept almost constant when the stoichiometric ratios of drug to organic amine were varied from 1:1 to 1:100. These results suggested that TEF and LOX have been integrated sufficiently into ion pairs at the equimolar ratio.

In addition, UV-Vis, ESR spectra in solution, and X-ray crystallography also have been employed for measuring the electronic changes in ion-pair formation process (Lü et al. 2005; Pal et al. 2010). Hudson et al. (1972) found that when weak acidic 3,4-dinitrophenol encountered organic amines at different molar ratio, a series of characteristic bathochromic shifts in UV absorption spectra were presented in going from free acid to a hydrogen-bonded complex, to an ion pair, to a solvated ion pair or a solvated anion. Lü et al. (2005) determined the crystal structures of pure ion-pair salts K(L_C)⁺//DNB⁻ and K(L_E)⁺DNB⁻ by X-ray crystallography. In the near-IR spectral analysis, they found that there were the same patterns of vibronic progressions for distinguishing the “separated” from the “contact” ion pair in both of the crystalline solid state and THF solution state, which ensured that the same X-ray structures persist in solution. Most importantly, in this study, the labilities of these dynamic ion pairs in solution were thoroughly elucidated by the temperature-dependent ESR spectral changes. Compared with other methods, X-ray crystallography can provide definitive structural information via analyzing the diffraction pattern of single crystal ion-pair salts. In another study, Fang et al. (2004) prepared the crystals of ion-pair complexes with an equimolar ratio of mefenamic acid (MH) and alkanolamines by removing the solvent in vacuo and subsequently confirmed that these complexes were associated with hydrogen bonds using X-ray crystallography (Fig. 13.4).